Semczuk Andrzej, Miturski Roman, Skomra Danuta, Jakowicki Jerzy A
2nd Department of Gynecology, University School of Medicine, 8 Jaczewski Street, 20-954, Lublin, Poland.
Arch Gynecol Obstet. 2004 Jan;269(2):104-10. doi: 10.1007/s00404-002-0449-6. Epub 2002 Nov 22.
Derailments of the control mechanisms in the G1/S phase of the cell cycle play a fundamental role in the initiation and progression of cancer. However, only a few reports have addressed the issue of simultaneously occurring abnormalities of Rb-pathway components in malignant endometrial tumors.
Currently, we assessed the expression of cell-cycle regulatory proteins (pRb, cyclin D1, p16(INK4A) and cdk4) in 48 sporadic endometrial cancers, and investigated these tumors for a possible relationship between aberrant protein staining and clinicopathological variables of cancer and RB-LOH.
There was abnormal pRb, cyclin D1, p16(INK4A) and cdk4 immunoreactivity in 2%, 50%, 6% and 25% of cases, respectively. Altogether, 33 of 48 (69%) endometrial malignant tumors showed abnormal expression of at least one Rb-pathway protein immunohistochemically. However, there was significant correlation neither between the cell-cycle regulators nor between the frequency of pRb, p16(INK4A) and cyclin D1 abnormalities and clinicopathological variables of cancer, but a significant correlation did exist between cdk4 staining and the clinical stage of disease ( P<0.05, Fisher's exact test). Moreover, an inverse relationship was also demonstrated between cdk4 expression and patient age ( r=-0.367; P=0.01). However, none of the cell-cycle regulatory proteins, except for pRb, was related to loss of heterozygosity at locus 13q14.
As a conclusion, derailments of the Rb-pathway components, cyclin D1 and cdk4 in particular, seems to participate in the endometrial cancer development in humans. Overexpression of cdk4 was related to the progression of neoplastic disease and corresponds with age of onset, suggesting a major role of altered cdk4 immunoreactivity in the progression of endometrial cancer.
细胞周期G1/S期调控机制的紊乱在癌症的发生和发展中起着根本性作用。然而，仅有少数报告探讨了恶性子宫内膜肿瘤中Rb通路成分同时出现异常的问题。
目前，我们评估了48例散发性子宫内膜癌中细胞周期调节蛋白（pRb、细胞周期蛋白D1、p16(INK4A)和细胞周期蛋白依赖性激酶4）的表达情况，并研究了这些肿瘤中异常蛋白染色与癌症临床病理变量及RB基因杂合性缺失之间的可能关系。
分别有2%、50%、6%和25%的病例出现pRb、细胞周期蛋白D1、p16(INK4A)和细胞周期蛋白依赖性激酶4免疫反应异常。48例（69%）子宫内膜恶性肿瘤中，共有33例免疫组化显示至少一种Rb通路蛋白表达异常。然而，细胞周期调节蛋白之间，以及pRb、p16(INK4A)和细胞周期蛋白D1异常频率与癌症临床病理变量之间均无显著相关性，但细胞周期蛋白依赖性激酶4染色与疾病临床分期之间存在显著相关性（P<0.05，Fisher精确检验）。此外，细胞周期蛋白依赖性激酶4表达与患者年龄之间也呈负相关（r=-0.367；P=0.01）。然而，除pRb外，其他细胞周期调节蛋白均与13q14位点的杂合性缺失无关。
总之，Rb通路成分的紊乱，尤其是细胞周期蛋白D1和细胞周期蛋白依赖性激酶4，似乎参与了人类子宫内膜癌的发生发展。细胞周期蛋白依赖性激酶4的过表达与肿瘤疾病进展相关，且与发病年龄相符，提示细胞周期蛋白依赖性激酶4免疫反应性改变在子宫内膜癌进展中起主要作用。
